Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- C19-position substituted geldanamycin derivatives, ESCC, HSP90, NQO1, NRF2-NQO1-activated cancer,
- MeSH
- Benzoquinones * pharmacology chemistry MeSH
- NF-E2-Related Factor 2 * metabolism genetics MeSH
- Humans MeSH
- Lactams, Macrocyclic * pharmacology chemistry therapeutic use MeSH
- Mice, Nude MeSH
- Mice MeSH
- NAD(P)H Dehydrogenase (Quinone) * metabolism genetics MeSH
- Cell Line, Tumor MeSH
- Esophageal Neoplasms * drug therapy metabolism genetics MeSH
- HSP90 Heat-Shock Proteins antagonists & inhibitors metabolism MeSH
- Antineoplastic Agents pharmacology chemistry MeSH
- Esophageal Squamous Cell Carcinoma * drug therapy genetics metabolism MeSH
- Xenograft Model Antitumor Assays * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Benzoquinones * MeSH
- NF-E2-Related Factor 2 * MeSH
- geldanamycin MeSH Browser
- Lactams, Macrocyclic * MeSH
- NAD(P)H Dehydrogenase (Quinone) * MeSH
- NFE2L2 protein, human MeSH Browser
- NQO1 protein, human MeSH Browser
- HSP90 Heat-Shock Proteins MeSH
- Antineoplastic Agents MeSH
In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity. As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione conjugation-mediated hepatotoxicity. In this study, using a variety of in vitro and in vivo cancer models, we found that C19-substituted 17DMAG compounds maintain their enhanced toxicity profile and synthetic lethal interaction with NRF2-NQO1-activated cancer cells. Importantly, using a xenograft mouse tumor model, we found that C19-substituted 17DMAG displayed significant anticancer efficacy against NRF2-NQO1-activated cancer cells without causing hepatotoxicity. These results clearly demonstrate the improved clinical potential for this new class of HSP90 inhibitor anticancer drugs, and suggest that patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.
Department of Organic and Bioorganic Chemistry Charles University Hradec Králové Czech Republic
Department of Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora CO USA
Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
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